Previous clinicopathological studies have indicated that some elderly individuals have numerous cerebral amyloid deposits, yet remain cognitively intact, a process we call "pathological aging" (PA). It remains uncertain if PA is pre-clinical Alzheimer's disease (AD), but the proposed studies i n the application will address this issue. In particular, clinicopathologic correlations with increasingly sophisticated neuropsychologic measures, such as those developed in Project 2, will be applied to determine if there are cognitive differences between PA and brains with no amyloid deposition. If PA is pre-clinical AD, it will be important to understand the nature of the amyloid that is deposited and the mechanism of its formation, especially if it is one of the earliest markers of AD. While tau pathology in PA is minimal, it will be important to precisely define the nature of tau pathology in PA as well as in cases with cognitive impairment ranging from mild amnestic deficits (amnestic cognitive impairment - ACI) to frank dementia. In this competing renewal, Specific Aim 1 is focused on characterizing amyloid in PA compared to AD, as well as studying the mechanism of amyloid deposition. Specific aim 2 is focused on the hypothesis that progressive tau pathology underlies cognitive impairment in ACI and AD. Studies in this aim will use quantitative analyses and a panel of tau antibodies, including recently developed antibodies specific to exon 10 splice forms of tau, to study progressive abnormalities in tau. Since most clinicopathologic studies of community residing subjects indicate that mild cognitive impairment and AD is often associated with mixed degenerative and vascular pathology, Specific aim 3 is focused on efforts to better characterize vascular pathology in brains to understand the relative contribution of vascular and degenerative lesions to cognitive impairment in the elderly. It will do so through development of novel quantitative assays of white matter pathology and arteriosclerotic vascular disease. In summary, the clinicopathologic correlations that form the underpinnings of this project focus on quantitative analyses of the three major structural pathologies in the aging brain - amyloid, tau and vascular disease.